5-(2-oxo-2, 5-dihydro-4-furyl)-benzo(b)-furans and intermediates therefor



United States Patent (2 0X0 2,5 DIHYDRO 4 FURYL) BENZO(b)- FURANS ANDINTERMEDIATES THEREFOR Josef Schmitt, LHay-les-Roses, France, assignorto Etablissements Clin-Byla, Paris, France, a company of France NoDrawing. Filed Feb. 1, 1965, Ser. No. 429,642 Claims priority,applicztiogmFranee, Feb. 7, 1964,

11 Claims. ci. 260343.6)

This invention relates to derivatives of furan and to a method for theirpreparation. In particular the invention provides a new series of furanderivatives having wherein R represents a lower alkyl radical, Rrepresents a hydrogen atom or a lower alkoxy radical and Y representsthe radical in which R represents a lower alkyl radical, anunsubstituted phenyl radical or a phenyl radical having in one or moresubstitution positions, a hydroxyl radical, a lower aliphatic esterradical or a lower alkoxy radical (including a tertiaryamino-substituted alkoxy radical) and R represents a hydrogen atom, alower alkyl radical or a monoor dicarboxylic acyl radical.

The lower alkyl radicals may be linear or branched (particularly thelower alkyl radical represented by R and the monoor dicarboxylic acylradical represented by R, is preferably a lower aliphatic acyl radicalbut other acyl radicals may also be present. The tertiary aminecomponent of the tertiary amino-alkoxy radical maybe aliphatic orcyclic.

From the viewpoint of the method of preparation, the compounds of. the.invention may be divided into two sub-series having the two generalformulae below:

lCe

in which R R R and R have the same significance as above.

The compounds of the present invention are therapeutics and possess oneor more of the following three types of therapeutic activity,coronary-dilat-ant, cardiotonic or hypotensive activity. The degree andtype of activity for a particular compound depend upon the nature of thesubstituents.

The invention consequently includes a pharmaceutical composition fororal or parenteral administration which comprises, as the activeingredient, a compound of the formula (A) above in admixture with apharmaceutically acceptable diluent or carrier.

One may prepare the compounds of the invention by starting fromp-methoxy phenyl butenolide, i.e. 4-(4- methoxy phenyl) 2-oxo2,5-dihydro furan, or from the corresponding lower alkoxy derivatives,i.e. starting with compounds corresponding to the formula in which R hasthe significance indicated above. p-Methoxy phenyl butenolide (R '=H) isdescribed by E. R.

2 of the benzene ring may be prepared by an analogous method.

The invention includes a method of preparation of compounds of Formula Icomprising three successive stages summarised in the followingequations, in which the symbols have the significance already indicated,and X stands for an halogen atom, especially a chlorine atom:

m-c-x 6 a v 4; 1H t p A10] H300 R3 3 HO Ra 0 Rr-o-onzX R1(') 8 HO R3K2003 The intermediate compounds corresponding to Formulae III and IVhave not previously been described and are included in the presentinvention.

The first reaction, which leads to a phenolic ketone (III) takes placeby reaction of an acid halide, particularly the chloride, with thealkoxy phenyl butenolide in the presence of a Friedel-Crafts type ofcatalyst such as aluminum chloride, preferably in an appropriate diluentsuch as methylene chloride, dichlorethane or nitrobenzene, oralternatively in the presence of an excess of the acid halide used asthe reactant. The reaction temperature may vary between room temperatureand 70 C.; the time taken does not normally exceed ten hours.

Typical hydroxyketones prepared in the first stage are summarised in thefollowing table, which includes 2. reference to the examples quotedlater on.

The second stage consists of the condensation of the phenolic hydroxylwith an a-h-alogeno ketone R COCH X, in which X stands for a halogenatom and R at lower alkyl radical or a phenyl radical, which may have alower alkoxy-substituent in one or more of its free positions.

The reaction may be carried out in a diluent, particularly dimethylformamide, in the presence of an alkali carbonate, for example potassiumcarbonate; the dimethyl formamide solubilises the alkali salts ofhydroxy ketones and permits the reaction to take place in a homogeneousmedium. One may operate at temperatures between room temperature and 50C. If the halogeno-ketone used is a chloro or a bromo-ketone, one mayincrease its reactivity by adding totheimedium a small quantity of analkali metal-iodide" which transiently forms the corresponding organiciodo-ketone.

Typical compounds of Formula IV are enumerated in Table II.

The third reaction which leads to certain of the compounds covered byFormula I takes place on more or less prolonged heating e.g. on a waterbath, of compounds of Formula IV in the presence of a mineral acidreagent, for example hydrochloric acid. This technique is related to oneof the general methods of synthesis of benzofurans (Chemistry of CarbonCompounds 1957, edited by E. H. Rodd, Volume IV A, page 170).

One may operate without a diluent, but preferably,

with a diluent such as ethyl alcohol, acetic acid or dimethyl formamide.There is often an advantage in not isolating the intermediates (IV) andconsequently directly acidifying the solution containing them to causetheir cyclisation, with the formation of a benzofuran ring system.

Finally, in order to obtain compounds of Formula I in which R is amonoor polyhydroxyphenylradical, it is necessary to dealkylate(generally demethylate) a compound of the Formula IV in which R is analkoxysubstituted phenyl radical by means of a dealkylation agent,preferably aluminium chloride, in an inert diluent such as refluxingbenzene. The period of heating varies but does not normally exceed tenhours. The resultant phenolic hydroxyl radical or radicals may besubsequently acylated by heating with an excess of an acid anhydride, oretherified to introduce a difierent alkoxy radical, for

" example a tertiary amino-alkoxy radical. Etherification to formatertiary amino-alkoxy groups is preferably carried out in a diluentsuch as dimethyl formamide, using a tertiary amino-alkyl halide as thealkylation agent, and in 7 8 TABLE III Continued r F 1 151 liiggtgg' R1R2 R5 (CB Nos.)

P 39 4075 H3C-HzC-- HOQ H- 40 4120 HaC-HzC-HzC- mooQ 11- The inventionalso includes a method of preparing compounds having the Formula IIwhich comprises subjecting the ketones of Formula I to controlledreduction carried out in methanol or, for products which dissolvewithdifficulty in methanol, in a mixture of diluents comprising methanol anda diluent such as ethyl acetate,

methylene chloride, dimethyl tormamide, dioxane or The reactiontemperature used is preferably close to room temperature; the timerequired for the reaction does not normally exceed a few hours. Thereaction results in secondary alcohols (R =H) and these may beesterified with a monobasic or dibasic acid. The reaction may be carriedout by warming the secondary alcohols with the appropriate acidanhydride, used by itself or in the presence of pyridine. The secondaryalcohols may also be ethenfied to form a lower aliphatic alkoxy radical,and this is done via a halogenated alkyl derivative which is caused toreact with the desired alcohol.

water. Table IV summarises typical compounds of Formula 11.

TABLE IV -O\:O l

m-c n 0/ R3 Example Identification No. es. R1 R4 R3 R4 (CB Nos.) 7

41 3574 ]130- H3C H- H- 42 3865 H5C- H- H H5C-OO 43 4091 H3C H3C-- HHOOCHZCH2GOC 44 3039 H5C- H;CH 0 H H- 45 3540 H5CHQC H C- H- H- 3877H3OH1C H5C- H H3OH2O-H;4OOC 3984 H3C-H2C -H 3C H HOOC--H2CHzC-OC 3887H3C-H2C HaC- H H3C' 3505 H5CHzC-H2C H5C H- H 3070 H5G-HYO-Hz0-Hz0 H30 H-H- 3583 H5CHC H3C H5CO- H 4010 (H C)2HCHzC H3C- I H- H- 4103 H5C- HgcOQ- 11- H 54 4033 HaC-HgC 1150 o H 11- 55 4054 HsC-HgC- HO-Q H- 11 4083H3c11c H- 11- i 0on3 57 4025 Inc-mo- T filo 0-Q H H- TABLE IVContinuedExample Identification N0. NOS. R1 R3 R3 R4 (CB Nos.)

58 4141 H3CHgC- mmo- H-- H- l H5020 H3510 as 405s mo-mo- H3O o-G- H-- H-60 4211 mo-mo-mc- H 0-- H-- H- The following examples illustrate theinvention. The EXAMPLE 4 abbreviations MP and MP refer to the meltingpoint 3 Val l d M he I 2 0x0 254,71 dro um (degrees C.) measuredrespectively in a capillary tube ery y r y f and on a Kofler bench. Thetemperatures are all in degrees centig-rade.

EXAMPLE 1 4-(3-acetyl 4-hydr0xy phenyl) 2-0x0 2,5-dihydro furan (1567CB) (a) A solution of 57 g. of 4-(4-methoxy phenyl) 2-oxo 2,5-dihydrofuran (0.3 mole) in 300 ml. of methylene chloride is added slowly to 200g. of anhydrous powdered aluminium chloride, whilst stirring and coolingin a bath of iced water. When this is completed, one removes the bathand leaves the reagents in contact for minutes, and then introduces 72g. of acetyl chloride at a speed sufiicient to maintain refluxing of thesolvent. One subsequently heats under reflux for 3 hours 30 minutes,decomposes by pouring on to crushed ice, filters off the crystallineproduct and washes it with water. 56 g.; MP =200 C. yield: 80%. Theproduct is recrystallised from acetic acid and then melts at 201202 C.

(b) Operating as under (a) but replacing the methylene chloride bydichlorethane, one obtains compound 1567 CB in the same yield.

(0) 36 g. of aluminium chloride and 21 g. of acetyl chloride are addedto ml. of nitrobenzene and thereafter 10 g. (0.0527 mole) of4-(4-methoxy phenyl) 2-oxo 2,5-dihydro furan dissolved in 50 ml. ofnitrobenzene are added drop by drop, with stirring. One warms for 2hours at 60-70 C., cools, pours on to'crushed ice, dilutes with etherand filters. 8 g. of product are obtained (yield: 65%). MP =200 C.

EXAMPLE 2 4-(3-propionyl 4-hydroxy phenyl) 2-0x0 2,5-dihydr0 furan (1575CB) 8 g. of anhydrous powdered aluminium chloride is added in stages toa solution of 3.8 g. (0.02 mole) of 4-(4- methoxy phenyl) 2-oxo2,5-dihydro furan in 20 ml. of propionyl chloride. The mixture is heatedfor one hour at 70 C., subsequently cooled and poured on to crushed ice,filtered and the residue crystallised from acetic acid. MP =213 0.;yield: 65%.

EXAMPLE 3 4-(3-butyryl 4-hydroxy phenyl) 2-oxo 2,5-dihyar0 furan Oneproceeds as in Example 2 but replacing the propionyl chloride by butyrylchloride in equivalent amount. MP =158159 C. (from acetic acid); yield:44%.

One proceeds as in Example 2 but replacing the propionyl chloride byvaleryl chloride in equivalent amount. Yield 40%. The productcrystallises from ethanol and melts at 139l40 C. (MP

EXAMPLE 5 4-(3-isovaleryl 4-hydroxy phenyl) 2-0x0 2,5-dihydro furan 4001CB) One proceeds as in Example 2 but replacing the propionyl chloride byisovaleryl chloride in equivalent amount. Yield: 40%. MP,,=128-l29 C.(from ethanol).

EXAMPLE 6 4-(4-hydr0xy Z-methoxy S-propionyl phenyl) 2-0x0 2,5- dihydrofuran (2774 CB) 30 g. of propionyl chloride and 35 g. of aluminiumchloride are added to 40 ml. of nitrobenzene and followed EXAMPLE 74-[3-acetyl 4-(2-0x0 propyloxy) phenyl] 2-0x0 2,5-dihydr0 furan 5.45 g.(0.025 mole) of compound 1567 CB (prepared according to Example 1)dissolved in 50 ml. of dimethyl formamide is stirred at room temperaturefor 15 minutes with 5 g. of potassium carbonate and 1 g. of sodiumiodide, and 5 g. of chloracetone are then added drop by drop. Thetemperature spontaneously rises a few degrees. The disappearance of thephenolic compound is checked by testing with an alcoholic solution offerric chloride; this test should be negative at the end of the reaction(approximately 2 hours). One then dilutes with 10 volumes of water,filters the product which crystallises out under these conditions andrecrystallises it from acetic acid. It has the form of yellow needles (4g. yield: 63%). MP =-l57 C.

EXAMPLE 8 4-[3-acetyl 4-(2-0x0 butyloxy) phenyl] Z-oxo 2,5-dihydro furanOne proceeds as in Example 7 but replacing the chlor acetone by l-bromo2-oxo butane in equimolecular quantity. MP =l3ll32 C. (from methanol).Yield: 66%.

EXAMPLE 9 4-[3pr0pi0nyl 4-(2-0x0 propyloxy) phenyl] 2-0x0 2,5-dihydrofur-an EXAMPLE 1O 4-[3-buzyryl 4-(2-0x0 propylaxy) phenyl] Z-oxo2,5-dihydr fur-an One proceeds as in Example 7 but replacing 1567 CB by2666 CB in equimolecular amount. MP =134 C. (from ethanol). Yield: 70%.

EXAMPLE 11 4-[3-valeryl 4-(2-0x0 propyloxy) phenyl] 2-0x0 2,5-dihydr0fm'an.

One proceeds as in Example 7 but replacing compound 1567 CB by 2667 CBin equimolecular amount. MP 138 C. (from methanol). Yield: 59%.

EXAMPLE l2 4-[3-is0valeryl 4-(2-0x0 propyloxy) phenyl] Z-oxo 2,5-dihydrofuran One proceeds as in Example 7 but-.replacing compound 1567 CB by4001 CB in equimolecular amount. MP 108 C. (from methanol). Yield: 58%.

EXAMPLE '13 4-[2-methaxy -propi0nyl 4-(2-0x0 propyloxy) phenyl] 2-0x02,5-dihya'ro furan One proceeds as in Example 7 but replacing compound1567 CB by 2774 CB in equirnolecular amount. MP 190 C. (from aceticacid). Yield: 75%.

EXAMPLE 14 4-[3acetyl 2-(3,4-dimeth0xy phenyl) 4-(2-0xo ethyloxy)phenyl] 2-ox0 2,5-dihydro furan EXAMPLE 15 4-[3-pr0pi0nyl 2-(4-methoxyphenyl) 4-(2-0x0 ethyloxy) phenyl] Z-oxo 2,5-dihydr0 furan One proceedsas in Example 14 but replacing compound 1567 CB by 1575 CB inequimolecular amount, and replacing the l-bromacetyl 3,4-dimethoxybenzene by l-bromacetyl 4-methoxy benzene in equimolecular amount. MP=174 C. (from acetic acid). Yield: 63%.

EXAMPLE 16 4-[3-pr0pionyl Z-(Z-methoxy phenyl) 4-(2-0x0 ethyloxy)phenyl] 2- x0 2,5-dihydr0 furan One proceeds as in Example 14 butreplacing compound 1567 CB by 1575 CB in equim'olecular amount, andreplacing l-bromacetyl 3,4+dimethoxy benzene by l-bromacetyl Z-methoxybenzene in equimolecular amount. MP =187188 C. (from acetic acid).Yield: 62%.

12 EXAMPLE 17 4-[3-pl opionyl 2-(3,4-dimethoxy phenyl) 4-(2-ox0ethyloxy) phenyl] 2-0x0 2,5-dihydro furan One proceeds asin Example 14but replacing compound 1567 CB by 1575 CB in equimolecular amount. MP197 C. (from acetic acid). Yield: 92%.

EXAMPLE 18 4-[3-pr0pi0nyl 2-(3,4,5-trz'meth0xy phenyl) 4-(2-0x0 ethyloxyphenyl] 2-0x0 2,5-dihydr0 fur-an One proceeds as in Example 14 butreplacing compound 1567 CB by 1575 CB in equimolecular amount andreplacing l-bromacetyl 3,4-dimethoxy benzene by 1-brom acetyl3,4,5-trimethoxy benzene in equimolecular amount. MP =254 C. (fromacetic acid); yield: 33%.-

EXAMPLE 19 Z-acetyl 3-methyl 5-(2-0x0 2,5-dz'hydro 4-furyl) benzo [b]furan (3556 CB) (a) A suspension of 2 g. of the compound preparedaccording to Example 7, in 20 ml. of concentrated hydrochloric acid, isheated to about 50 C., just until it dissolves. Thereafter it is heatedfor 2 minutes to 70 C., just until precipitation commences. The mixtureis allowed to cool, diluted with water, filtered, the residue washed,dried, and sublimed at 200 C. and 0.1 mm. pressure. 1.4 g. of product(yield: 70%) is obtained. MP =218 221 C. A second sublimation produces achemically pure productnMP 221-222 C.

(b) Compound 1567 CB and chloracetone are caused to react as in Example7, the mineral salts subsequently filtered, 12 ml. of concentratedhydrochloric acid are added to the solution in dimethyl formamidewithout dilution withwater, and the mixture heated for 40 minutes on awater bath. The product crystallises in the warm mixture, the mixture iscooled to room temperature, filtered, the residue washed with water andcrystallised from acetic acid. MP =222 C. Yield: 60% based on compound1567 CB.

' EXAMPLE 20 Z-propz'onyl 3-methyl 5-(2-0xo 2,5-dihyaro 4-furyl) benzo[b] furan (3638 CB) One proceeds as indicated in Example 19a, replacingthe compound prepared according to Example 7 by that prepared accordingto Example 8. MP =221 C. (from acetic acid); yield: 60%.

EXAMPLE 21 Z-acetyl 3-pr0pyl 5- (2-0x0 2,5-dihydr0 4-fmyl) benzo [b]furan (3671 CB) 7 v One proceeds as in Example 19a but replacing thecompound prepared according to Example 7 by an equimolecular amount ofthe compound prepared according to Example 10. MP =173 C. (frommethanol; yield: 50%.

EXAMPIJE 23 2-acetyl 3-butyl sz-oxo' 2,5-dihyd'ro 4-furyl) benzo [b]furan (3672 CB) A solution of 0.02 mole of the compound preparedaccording to Example 11, in 12 ml. of acetic acid, is heated" 13 toboiling and 12 ml. of concentrated hydrochloric acid then added. Themixture is maintained at the boil for about 2 minutes, cooled, dilutedwith water, the crystallised product filtered E and recrystallised fromethanol. MP =155 0; yield: 60%.

EXAMPLE 24 Z-acelyl 3-is0butyl -(2-oxo 2,5-dihydro 4-furyl) benzo [b]furan One proceeds as in Example 19a but replacing the compound preparedaccording to Example 7 by the compound prepared according to Example 12.MP =207 C. (from acetic acid); yield: 80%.

EXAMPLE 25 Z-acetyl 3-ethyl 5-(2-oxo 2,5-aihydro 4- uryl) 6-meth0xybenzo [b] furan (3676 CB) One proceeds as in Example 23 but replacingthe compound prepared according to Example 11 by an equimolecular amountof the compound prepared in Example 13. MP=254 C. (on a heated platemicroscope);

\ yield: 80%.

EXAMPLE 26 3-methyl 2-veratr0yl 5-(2-0x0 2,5-dihydro 4-furyl) benzo [b]furan (4245 CB) EXAMPLE 27 2-(3,4-dz'hydroxy benzoyl) 3-merhyl 5-(2-0xo2,5- dihydro 4-furyl) benzo [b] furan (4106 CB) g. of compound 4245 CBprepared according to Example 26, in 100 ml. of anhydrous benzene,together with 27 g. of anhydrous aluminium chloride, are heated underreflux for 8 hours. The mixture is cooled, poured on to ice, filteredand recrystallised first from acetic acid and then from ethanolcontaining 40% Water. MP=280 C. (with decomposition, heated platemicroscope); yield: 20%.

EXAMPLE 28 Z-anisoyl 3-ethyl 5- (2-0x0 2,5-dihydro 4-furyl) benzo [b]furan (4032 CB) One proceeds as in Example 26 but replacing, in thatmethod, the product prepared according to Example 14 by the productprepared according to Example 15.

MP =202-203 C.; yield: 86%

EXAMPLE 29 2-(4-hydroxy benzoyl) 3-ethyl 5-(2-0x0 2,5-dihydro 4-furyl)benzo [b] furan (4030 CB) One proceeds as in Example 27 but replacing,in that method, compound 4245 CB by 4032 CB. The instantaneous meltingpoint is 290 C. (with decomposition on the heated plate microscope);yield: 69%.

EXAMPLE 30 2-[4-(2-diethylamz'no ethoxy) benzoyl] 3-ethyl 5-(2-oxo2,5-dihydro 4-furyl) benzo [b] furan (4053 CB) 1 g. of potassiumcarbonate is added to a solution of 1 g. of compound 4030 CB in 20 ml.of dimethyl formamide, and stirred for minutes. One then adds 1.2 g. ofl-chloro Z-diethylamino ethane. The mixture is stirred at roomtemperature for 4 hours then poured into water and extracted with ethylacetate. One washes with water, evaporates the solvent and crystallisesfrom methanol; 0.6 g. are obtained; yield: 46%. MP =121 C. The ChlOl'!14 hydrate, crystallised from ethanol, melts at 210 C. (MP

EXAMPLE 31 2-[4-(2-dimethylamino l-methyl ethoxy) benzoyl] 3-ethyl5-(2-0xo 2,5-dihydr 4-furyl) benzo [b] furan (4246 CB) One proceeds asin Example 30 but with the following modifications: 1-ch1oroZ-diethylamino ethane is replaced by l-dimethylamino 2-chloro propaneand one heats at 50 C. for 2 hours after addition of the amine reagent.After extraction with ethyl acetate and evaporation of the solvent, theproduct obtained is purified via its chlorhydrate. The base, liberatedby addition of a sodium carbonate solution to the chlorhydrate, finallymelts at 129 C. (MP from methanol); low yield.

EXAMPLE 32 Z-(Z-methoxy benzoyl) 3-ethyl 5-(2-0x0 2,5-dihydr0 4-furyl)benzo [b] furan (4079 CB) One proceeds as in Example 26 but replacing,in that method, the product prepared according to Example 14 by theproduct prepared according to Example 16. MP C. (from acetic acid);yield is practically quantitative.

EXAMPLE 33 2-salicyl0yl 3-ethyl 5-(2-0x0 2,5-dihydro 4-furyl) benzo [b]furan (4085 CB) One proceeds as in Example 27 but replacing, in thatmethod, compound 4245 CB by 4079 CB. Yield: 69% MP =258 0.

EXAMPLE 34 2-veratr0yl 3-ethyl 5-(2-ox0 2,5-dihydro 4-furyl) benzo [b]furan (3970 CB) 14 g. of potassium carbonate are added to a solution of14 g. of compound 1575 CB in 100 ml. of dimethyl formamide; after 15minutes of stirring 16.7 -g. of l-bromoacetyl 3,4-dimethoxy benzene areadded. The temperature spontaneously rises a few degrees; the mixture isthereafter heated for 30 minutes at 50 C. and at 70 C. for a briefperiod, and the insoluble mineral salts are filtered hot; 55 ml. ofconcentrated hydrochloric acid are added to the solution which has beenfreed of its salts, the mixture heated for 2 hours on the water bath,cooled, and the crystalline product filtered. A second fraction of theproduct is obtained by diluting its mother liquor with water. The twofractions are combined and together crystallised from acetic acid. MPC.; yield: 80% (based on 1575 CB).

EXAMPLE 35 2-(3,4-dieth0xy benzoyl) 3-ethyl 5-(2-ox0 2,5-dikydr04-furyZ) benzo [b] furan (4140 CB) One proceeds as in Example 34 butreplacing 1- bromacetyl 3,4-dimethoxy benzene by l-bromaceytl 3,4-diethoxy benzene in equirnolecular amount. Yield: 54%. MP =208 C.

EXAMPLE 36 2-(3,4-dihydr0xy benzoyl) S-ethyl 5-(2-0x0 2,5-dihydro4-furyl) benzo [b] furan (4061 CB) One proceeds as in Example 27 butreplacing compound 4245 CB by an equimolecular amount of compound 3970CB. Yield 53%: MP=265267 C. (heated plate microscope) EXAMPLE 3727(3,4-diacet0xy benzoyl) 3-ethyl 5-(2-0x0 2,5-dihydro 4-fu1 yl) benzo[b] furan (4070 CB) 2 g. of compound 4061 CB are refluxed in 40 m1. ofacetic anhydride for 3 hours. The excess anhydride is 75 distilled oilin vacuo and the residue crystallised from ethyl acetate. 1.6 g. ofcompound 4070 C3 are obtained. Yield: 64%. MP =l83l84- C.

EXAMPLE 3 8 2-(3,4,5,-trimethoxy henzoyl) 3-ethyl 5-(2-0x0 2,5-dihydro4-furyl) benzo [b] furan (4055 CB) One proceeds as indicated in Example.26 but replacing the product made according to Example 14 by anequimolecular amount of the product made according to Example 18. Yield:78%. MP =223 C.

EXAMPLE 39 3-ethyl Z-galloyl 5-(2-0x0 2,5-dihydro 4-furyl) benza [b]furan (4075 CB) 7 One proceeds as in Example 27 but replacing compound4245 CB by an equimolecular amount of compound 4055 CB. Yield: 68%. MP=260 C. (from acetic acid).

EXAMPLE 40 2-veratroyl3-pr0pyl 5-(2-0xo 2,5-dihydro 4-furyl) benzo [b]fzmm (4126 CB) One proceeds as in Example 34 but replacing compound 1575CB by an equimolecular amount of compound 2666 CB. Yield: 40%. MP =218C.

EXAMPLE 41 2-(] -hydroxy ethyl) 3-methyl 5-(2-0xo 2,5-dihydr 4-juryl)benzo [b] furan (3574 CB) EXAMPLE 42 Z-(I-acetoxy ethyl) 3-methyl-(2-0x0 2,5-dihydr0 4-furyl) benzo [b] furan (3865 CB) 4.1 g. ofcompounds 3574 CB in 40 ml. of acetic anhydride are heated under refluxfor 5 hours; the excess anhydride is stripped in vacuo and the residuecrystallised from ethyl acetate. Yield: 47%. MP =l61-162 C.

EXAMPLE 43 2-(1-succinyloxy ethyl) S-methyl 5-(2-0x0 2,5-dihydr04-furyl) benzo [b] fut-an (4091 CB) 8.65 g. of compound 3574 CB in 43ml. of pyridine are warmed for 30 minutes, on a water bath, withsuccinic anhydride. At the end of this, the pyridine is stripped oil invacuo. The mixture is treated with dilute sulphuric acid and with ether,the crystalline product filtered off, washed with water and with ether,and recrystallised from ethyl acetate (9.35 g.). MP =144 C. (measuredafter drying at 90 C. and 0.1 mm.). Yield: 77%. The product yields anequimolecular compound with morpholine. MP :136" C. (from ethylacetate).

EXAMPLE 44 Z-(I-hydroxy propyl) 3-methyl 5-(2-0x0 2,5-dihydro 4-furyl)benzo [b] furan (3639 CB) EXAMPLE 4s 2-(1 -hydr0xy ethyl) 3-ethyl5-(2-ox0 2,5-dihydr0 4-furyl) benzo [b] furan (3640 CB) One proceeds asin Example 41- butreplacing compound 3556 CB by an equimolecular amountof 3641 CB. Yield: MP l84 C. (from ethanol).

EXAMPLE 46 I-(I-butyryloxy ethyl) 3-ethyl 5-(2-0x0 2,5-clihydr0 4-furyl)benzo [b] furan (3877 CB) 2 g. of compound 3640 CB in 20 ml. of butyricanhydride are heated at 150 C. for 6 hours. The excess anhydride isstripped in vacuo and the residue crystallised from a mixture ofcyclohexane and ether. 2 g. of product are obtained. MP =89 C.; yield:80%.

EXAMPLE 47 I 2-(1-succinyl0xy ethyl) 3-ethyl 5-(2-0xo 2,5-dihydr04-furyl) benz0[b]furan (3984 CB) One proceeds as in Example 43 butreplacing compound 3574 CB by an equimolecular amount of compound 3640CB. Yield 63%. MP =138140 C. (after drying the product at 90 C. and 0.1mm.). With morpholine this product yields an equimolecular compound ofMP =116-ll7 C. (from ethyl acetate).

EXAMPLE 48 2-(1-meth0xy ethyl) 3-ethyl 5-(2-ox0 2,5-dihydr0 4-furyl)benzo[b]furan (3887 CB) ether. 2 g. of product (3 8%) are obtained. MP=123 C.

EXAMPLE 49 Z-(I-hydroxy ethyl) 3-pr0pyl 5-(2-0x0 2,5-dihydr0 4-juryl)benz0[b];furan (3665 CB) One proceeds as indicated in Example 44 butreplacing compound 3638 CB by an equimolecular amount of compound 3671CB. MP =168 C. (from methanol). Yield: 66%.

Y EXAMPLE 50 2-(] -hydroxy ethyl) 3-butyl 5-(2-0x0 2,5-dz'hydro 4-furyl)benzo[b]furan (3670 CB) One proceeds as in Example 44 but replacingcompound 3638 CB by compound 3672 CB. MP :161 C. (from methanol). Yield:77%.

EXAMPLE 51 V Z-(] -hydr0xy ethyl) 3-ethyl 5-(2-0x0 2,5-dihydr0 4-furyl),6-methoxy benz o[b]furan (3688 CB) 3 g. of compound 3676 CB in ml. ofdioxane are treated with ml. of methanol and, adding a little at a time,2 g. of sodium borohydride. The mixture is poured into' dilute aceticacid, the solvents stripped in vacuo, theand 100 ml. of ethyl acetate.After having been in contact for 30 minutes, the mixture is poured intodilute acetic acid, the solvents stripped in vacuo, the residue dilutedwith water, filtered, the product washed with water and crystallisedfrom ethanol. 9.5 g. of product are obtained; yield 95%. MP 179 C.

EXAMPLE 53 [2-(3,4-dimethoxy phenyl)-hydr0xy-methyl] 3-methyl (Z-oxo2,5-dihydro 4-furyl) benzo[b]furan (4103 CB) One proceeds as in Example41 but with the following changes: compound 3556 CB is replaced by anequimolecular amount of compound 4246 CB and is left in contact with thesodium borohydride for 4 hours. MP =166167 C. (from ethyl acetate);yield: 73%.

EXAMPLE 54 2-(anisoyl-hydroxy-methyl) 3-ethyl 5-(2-0x0 2,5-dihydrofuryl-4) benz0[b] uran (4033 CB) One proceeds as indicated in Example 52but with the following changes: compound 4000 CB is replaced by anequimolecular amount of compound 4032 CB; the reduction is carried outin 20 volumes of ethyl acetate and 4 volumes of methanol and contactwith the sodium borohydride is allowed for 1 hour 30 minutes: MP =150151 C. (from ethyl acetate). Yield. 80%.

EXAMPLE 55 2-[(4-hydr0xy phenyD-hydroxy-methyl] 3-ethyl 5-(2-0x02,5-dihydr0 4-furyl) benzo[b]furan (4054 CB) 2 g. of sodium borohydrideare progressively added to 2.1 g. of compound 4030 CB in suspension in100 ml. of methanol and 50 ml. of water. The starting solid dissolvesgradually. The mixture is allowed to stand for 1 hour and then pouredinto very dilute sulphuric acid. It-

is filtered to remove an insoluble product and the filtrate concentrateddown to a small volume: on cooling, crystals deposit and these arerecrystallised from ethanol (0.8 g.).

MP =l90 C. (with decomposition). Yield: 38%.

EXAMPLE 56 2-[(2-eth0xy phenyD-hydroxy-methyl] 5-(2-0xo 2,5-dihydro4-furyl). benzo[b]furan (4083 CB) One proceeds as in Example 54 butreplacing com-- pound 4032 CB by an equimolecular amount of compound4079 CB. MP =208209 C. (from ethyl acetate); Yield: 80%.

EXAMPLE 57 2-[(3,4-dimeth0xy phenyl) -hyciroxy-methyl] 3-ethyl 5-(2- 0x02,5-dihydr0 4-furyl) benzo[b]furan (4025 CB) The reaction may also becarried out either in a mix-.

ture of 8 vol. of methylene chloride and 2 vol. of methanol, or in amixture of 5 vol. of dimethyl formamide and 2 vol. of methanol; theyields are a little lower.

EXAMPLE 58 2-[(3,4-dieth0xy phenyl)-hydr0xy-methyl] 3-ethyl 5-(2- 0x02,5-dihydro 4 furyl) benz0 [b]furan (4141 CB) One proceeds as in Example41 but replacing compound 3556 CB by an equimolecular amount of compound4140 CB. MP =l88 C. (from methyl ethyl ketone); yield 94%.

18 EXAMPLE s9 2-[(3,4,5-trimeth0xy phenyl)-hydroxy-methyl] 3-ethyl 5-(Z-oxo 2,5-dihydro 4-furyl) benz0[b]furan (4058 CB) One proceeds as inExample 57 but replacing compound 3970 CB by an equimolecular amount ofcomgog nd 4055 CB. MP =l78 C. (from ethanol). Yield:

EXAMPLE 6O 2 [(3/1 dimethoxy phenyl) -hydr0xy-methyl] 3-pr0pyil 5-(2-0xo 2,5-dihydro 4-furyl) benzo[b]furan (4127 CB) One proceeds as inExample 41 but replacing compound 3556 CB by an equimolecular amount ofcompound 4126 CB. MP =156-l57 C. (from ethyl acetate);

yield: 80%

PHARMACODYNAMIC INVESTIGATION The compounds of the Formulae I and IIhave been studied to assess their action on the blood supply tocoronary, visceral and peripheral blood vessels, their elfect onsystemic arterial blood pressure, and finally their possible effect onthe contraction of the cardiac muscle.

The following methods were used:

(1) Measurement of coronary supply, and of systemic arterial pressure.

These experiments were carried out with dogs weighing 10 to 15 kg. Afteradministering a general anaesthetic using urethane-chloralose, andclosed circuit artificial respiration, a thoracotomy was carried out inthe fifth intercostal space on the right, and the heart was exposedafter opening the pericardium and fixing it to the rib side. The dog wassubsequently treated with heparin to render the blood incoagulable. Aspecial probe was then introduced into the right superficial jugularvein and was pushed gently as far as the right auricle. The index fingerof the left hand of the operator then guides the end of the probe in theorifice of the coronary vein sinus by gentle pressure exerted across theside of the right auricle. When the probe is properly in position it ispossible to inflate, from outside the animal, a small rubber latexballoon which renders the system completely leak-tight and avoids any"leakage between the sides of the blood vessel and the probe; the supplyof blood leaving the coronary sinus can thus be measured by means of agraduated tube and a stop Watch. The blood leaving the graduated tube*is collected in a decanting flask and is then reinjected continuouslyinto the animal,. after having been re-heated to 39 C.

. ceral and peripheral vessels.

Most of the compounds investigated have shown a significant hypotensiveeffect, but some of them, particularly compound CB 4091, have attractedattention by their marked and prolonged hypotensive effect.

It has been checked that the hypotensive activity is displayed with'different species of animals (dog, cat, rabbit, rat) regardless ofwhether administered orally or parenterally, and whether the animalstreated were asleep or awake.

The mechanism of the observed hypotension was established by a study ofvarious phenomena: eflfect on the cardiac rhythm, effect on the actionof chemical agents, and finally a study of the variation of blood supplyin the blood vessels of different parts of the animal, by directmeasurement in the majority of experiments and by plethysmographicmethod in some cases.

These studies revealed that the mechanism of the hypotensive activitydisplayed by compound CB 4091 and related compounds is connected withthe relaxing action of these compounds on the smooth muscle of the.blood vessels of different parts of the animal. This action causes anincrease in the bore of the arterial and capillary vessels.

(3) Study of cardiotonic effect.

-The cardiotonic elfect was studied by two difierent methods:

(a) An in vitro method, using auricles isolated from guinea pigs.

Auricles isolated from all species of animals possess the property ofcontracting Spontaneously if maintained in a live state in aphysiological nutrient liquid at an appropriate temperature and Withsufiicient oxygen supply. With this type of preparation it is possibleto record graphically the ampitude and the rhythm of the contractions ofthe cardiac muscle.

For reasons of convenience, allowing a large number of experiments, andalso because of its sensitivity to cardiotonic substances, the guineapig was the species of 7 animal finally chosen.

placed below the right auriculo-ventricular sulcus. A constant tensionof the order of 150-180 grams, applied by an adjustable tension coilspring, isapplied-to the movable forceps. The movement is transmitted byan assembly of pulleys, and can be recorded graphically.

This method has the advantage of permitting the measurement not only ofthe maximum shortening of the myocardiac muscle fibre at the instant ofits contraction (positive inotropic eifect), but also the state of themuscle tone (tonotropic effect).

. Conclusions A number of the compounds studied have the interestingcharacteristic of simultaneously increasing the coronary supply and thecontraction of the myocardium. The majority of the compounds of thisgroup are hypotensive, with intensities of etfectwhich vary considerablyfrom one compound to the other, but in those cases where the predominantproperty is the hypotensive efiect, one nevertheless observes anoticeable coronaro-dilatant and cardiotonic activity.

The results are presented in two tables: the first table (Table V)comprises the ketonic products of chemical Table III. The second (TableVI) summarises the alcoholic compounds, and their derivatives, as listedin chemi-.

pair of forceps at the apex and a movable pair of forceps c l Table IV,

TABLE V Concentration or dose Coronarodilatant applied; method ofactivity administration; solvent (treating used papaverine Hypotensiveactivity (treating papaverine as 1) cardiotonic activity (treatingouabain as 1) Observations Efiect on the heart of a dog in situ Efiecton an isolated guinea pig auricle 1 X10- and 1 XIO' 1,2-pr0panediol.

3638 1,2-propenedlol 1X10 and 1 X10' 1 and 2 Inga/kg. i.v.

Augmented.

1 X1()- and 1 X10- 1 and 2 mgJkg. i.v. 1,2 propanedi0l.

Slightly decreased.

1 and 2 mgJkg. i.v. 1,2-propanediol.

V Unchanged.

1 )(10- and 1 and 2 mg.[kg. i.v. 1,2-propanedio1.

Unchanged.

1 X10 and 1 X10 1,2-propauediol.

1 X10- and 1 and ,2 ing/kg. i.v. 1,2-p1'0pauediol.

Unchanged.

1 X10- and 1 X 10 1,2-pr0panediol.

1 X10- and 1 X10- 1,2-pr0panediol.

2 mgJkg. i.v. 2. 7 water+0.5% acetic acid.

1,2-propanediol. 7

-35 percent.

2 mg./kg. i.v. 1. l5

1 ,2-propanedi0].

23 percent.

1- 10- and 2. 5 0. 1 X10- 1 mgJkg. i.v. 1,2-propanediol.

2 rngJkg. i.v. 1 I very slightly Soluble. 1,2-propanediol.

10 percent.

TABLE VContinued Concentration or dose" applied; method ofadministration; solvent used Coronarodilatant activity (treatingpapaverine as 1) Hypotensive activity (treating papaverine as 1)Cardiotonic activity (treating ouabain as l) Effect on an isolatedguinea pig auricle Effect on the heart of a dog in situ Observations 2mg./kg. i.v. 1,2-propanediol.

34 percent.

Toxicity LD 501.1). 700 mgJkg. LD p.o. 700 mgJkg.

35 percent.

1 XuH' and 1 X1 0' 1,2-propanediol.

40 percent.

2 mgJkg. i.v. 1,2-propanediol.

35 percent.

2 mgJkg. i.v. 1,2-pronanediol plus ethyl oleate.

24 percent.

TABLE VI Coronarodilatant activity (treating papaverine as 1)Hypotensive activity (treating papaverine Cardiotonic activity (treatingouabain as 1) Effect on an isolated guinea pig auricle Efiect on theheart of a dog in Situ Observations 1 X" and 1 ,2-propanediol.

Slightly lowered.

Toxicity (mouse) 0 -l p.o.

1,000 mgz/kg.

1 X10 and 1X10' 1,2rpropanediol.

1 X10- and 1 X10 1 and 2 mgJkg. i.v. WateH-NazCO Toxicity LD 50 (mouse)s.c.

335 mgJkg. p.o. =550.

1,2-propanedi0l 1 and 2 mgJkg. i.v.

Maximum increase.

1 X10- and 1 X101 1 and 2 mgJkg. 1,2-propanedio1.

Maximum increase.

Toxicity LD 50 (mouse) s.c.='

1,800 mgJkg.

1 X1 0- and 1 X10" 1 ,2-propanediol.

1 X10 and 1X10 5 mgJkg. i.v. water+propanediol water+Na CO3.

Toxicity (mouse) 300 mgJkg.

p. 400 mg.,/kg.

1X10' and 1 mgJkg. i.v. 1,2-propanediol.

Slightly lowered.

1 X10 and 1X10-5 1 mgJkg. i.v. 1,2rpropanediol.

Maximum increase.

1 and 2 mgJkg. i.v. 1,2-propanediol.

Slightly lowered.

2 mgJkg. i.v. 1,2-propanedio1.

2 mg./kg. i.v. very slightly soluble in 1,2-propanediol.

2 mgJkg. i.v. 1,2-propanediol.

TABLE VICon*tinued Cardiotonic activity (treating Concentration or doseCoronarodilatant Hypotensive activity ouabain as 1) applied; method ofactivity (treating papaverme v I N o. administration; solvent (treatingas 1) Observations used papaverine Effect on an Effect on the as 1)isolated guinea heart of a dog pig auricle in situ" 4033 1 10- and 1. 3830%. 0. 40

1 X 2 mgJkg. i.v. 1,2-propanediol.

4054 2 rug/kg. i.v. 0.92 -5D%.

1,2-propanediol.

4083 2 mgJkg. i.v. 1. 75 23%.

1,2-propa1rediol.

4085 2 ing/kg. i.v. 1. 23%.

1,2-propanediol. 4025 1 10- and 4. 2 45%. 0.50 0.10 Toxicity 1X10" LD 502 mg./kg. i.v. (mouse) 1,2-propanediol. l.v.=

75 mgJkg. i.p.=1,80- s.c.=1,500 p o =1,800

4141 2 mg./kg. i.v. 2. 4 -42%.

1,2-propanedi01.

4058 1X10- and 3. 8 45%. 0.37

1 X10- 1,?rpropanediol.

4127 2 mgJkg. i.v. 0.17 45%.

1,2-propanediol.

The compounds studied in the above tables have been shown, in general,to have a low degree of toxicity. For example, the toxicity of compounds4091 CB and 4025 CB, studied in mice by oral or hypodermicadministration and assessed by the method of Karber and Behrens, is asfollows:

For 4091 CB About mg./ kg. LD 50, by hypodermic administration 350 LD50, by oral administration 550 For 4025 CB LD 50, by hypodermicadministration 1500 LD 50, by oral administration 1800 Furthermore, someanimals have been treated daily, for three months at the rate of 60 mg.of 4091 CB by month per kg. or at the rate of 100 mg. of 4025 CB bymonth per kg. These animals behaved normally and no abnormality wasestablished in a histological study of the animals.

The compounds having the general formula (A) particularly 4025 CB or2-[3,4-dimethoxy phenyl)-hydroxymethyl] 3-ethyl 5-(2-oxo 2,5-dihydro4-furyl) benzo [b] furan and 4091 CB or Z-(I-succinyloxy-ethyl) 3-methyl5-(2-oxo 2,5-dihydro 4-furyl) benzo [b] furan have one or more of thefollowing therapeutic actions, namely vasodilatant, hypotensive, andcardiotonic activities and they can be utilised in medicine in thetreatment of the following conditions:

arteritis cerebral arteriosclerosis ulceration of the lower limbsmanifestations of arterial hypertension coronary syndromes.

It will be understood that the compounds of the invention could beassociated with therapeutic substances which complement the activity ofthe compounds of the in vention, such as sulphonamide diuretics orsubstances having a hypotensive eifect such as reserpine. The compoundsof the invention may be utilised in therapeutic medicine in dosage unitsof about 5 to 500 mg. in the form of tablets or in the form of asolution for intravenal or intramuscular injection (in cases where theselected compound is soluble in a pharmaceutically acceptable solvent).Among the compounds of the formula (A) are compounds such as 4091 CB,which are hemiesters oi succinic acid. Consequently, such compounds mayalso be marketed in the form of alkali metal salts, alkali earth metalsalts, pharmaceutically acceptable amine salts and examples of suitablesalts are: salts of sodium, potassium, magnesium, ammonium, pyrrolidine,morpholine, diethylamine and ethanolamine.

Examples of suitable pharmaceutical formulations are given below:

TABLETS Formulation I Mg. 2-(1-succinyloxy ethyl) S-methyl 5-(2-oxo2,5-dihydro-4-furyl) benzo [b] furan (4091 CB) 50 Pharmaceuticalexcipient Sufficient for a tablet.

Formulation II Mg. [2-(3,4-dimethoxy phenyl)-hydroxy-methyl] 3-ethyl5-(2-oxo 2,5-dihydro 4-furyl) benzol [b] furan (4025 CB) 250Pharmaceutical excipient Suflicient for a tablet.

The tablets are prepared according to the usual methods of doublecompression or granulation with the help of an aqueous solution of a gumor a non-aqueous solvent such as ethyl alcohol, The excipients used maybe, for example, starch, talc, gum arabic, magnesium stearate orcarboxymethylcellulose. The tablets may be rendered enteric byglutinisation or covering with a substance resistant to the action ofgastric juice such as cellulose acetophthalate with a view to preventingan action of stomach hydrochloric acid on the active principle oravoiding possible gastric disorders. The tablets may be enveloped in asugar or other coating, which is. opaque and may be coloured.

Formulations for injection The 2-(1-succinyloxy ethyl) 3-methyl 5-(2-oxo2,5- dihydro 4-furyl) benzo [b] furan (4091 CE) is dissolved in water,containing a slight stoichiometric excess of morpholine, e.g. for eachgram of 4091 CB 33 ml. of

1% aqueous solution of morpholine. After dissolving the compound at atemperature of about 4 C., the resultant solution is diluted with waterto a volume of about 50 ml., the solution is filtered on sterilisedfilter material and is filled for example into the ampoules in an amountof 0.5 ml. per ampoule. The solution is cooled and freeze driedaccording to the usual techniques.

Each ampoule prepared in these conditions contains 10 mg. of 4091 CB inthe form of morpholine salt, which is dissolved in distilled, sterilisedwater at the time of use.

At present the preferred compounds are 4091 CB and 4025 CB and theformer compound may be administered in the treatment of coronaritis andarteritis at a dosage rate of 200 to 400 mg. per day in tabletscontaining 50 mg. of the active ingredient, while the latter compoundmay be administered at a dosage rate of 250 to 1500 mg. per day intablets containing 250 mg. of the active ingedient.

What I claim is:

1. A furan compound having the formula:

Lit"

in which R represents a member of the group consisting of alkyl,unsubstituted phenyl, and substituted phenyl having from 1 to 3substituents selected from the group consisting of hydroxy, alkanoyloxy,alkoxy, and dialkylamino alkoxy, and R represents a member of the groupconsisting of hydrogen, alkyl, alkanoyl, and carboxy alkanoyl, each ofsaid alkyl, alkoxy, and alkanoyl having from 1 to 4 carbon atoms.

2. A furan compound of the formula:

it Mr,

wherein R R and R have the same significance as in claim 1.

(A) wherein 3. A furan compound of the formula:

in which R and R have the same significance as in claim 1, and Rrepresents a member of the group consist ing of alkyl, unsubstitutedphenyl, and substituted phenyl having three alkoxy substituents, saidalkyl and said alkoxy having from 1 to 4 carbon atoms.

11. A furan compound having the formula:

in which R and R have the same significance as in claim 1.

References Cited Rodd, Chemistry of Carbon Compounds, vol. IV A, p. QD251.R6.

Wagner et a1., Synthetic Organic Chemistry, pp. 171, 226-27, 317-18.

ALEX MAZEL, Primary Examiner. I. A. NARCAVAGE, Assistant Examiner.

1. A FURAN COMPOUND HAVING THE FORMULA